Pancreatic adenocarcinoma is an aggressive cancer with poor clinical prognosis and limited therapeutic options. There is a significant lack of effective, safe, and targeted therapies for successful treatment of pancreatic cancer. In this report, we describe the anticancer efficacy of two novel compounds, N-methylpiperazinyl diarylidenylpiperidone (L-2663) and its pro-nitroxide conjugate (HO-4589) evaluated on human pancreatic adenocarcinoma (AsPC-1) cell line and xenograft tumor in mice. Using flow cytometry, we determined the effect of the L-2663 and HO-4589 drugs in inducing mitochondrial toxicity, triggering cell-cycle arrest, and apoptosis. EPR spectroscopy was used to quantify cellular uptake, metabolic conversion and stability of HO-4589 in cells and in vivo monitoring of tumor oxygenation as a function of growth. The results established different antiproliferative efficacy of the L-2663 and HO-4589 compounds, with a targeted action on cancer cells while being less toxic to noncancerous cells. The study may have important implications in the future designs of safe and effective chemotherapeutic agents for the treatment of pancreatic cancer.

中文翻译：

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通过 ROS 介导的线粒体功能障碍和 G2/M 细胞周期阻滞在人胰腺癌中通过 N-甲基哌嗪基二芳基哌啶酮及其前氮氧化物偶联物选择性诱导细胞毒性和抗肿瘤功效。

胰腺癌是一种侵袭性癌症，临床预后较差，治疗选择有限。显着缺乏用于成功治疗胰腺癌的有效、安全和靶向疗法。在本报告中，我们描述了两种新型化合物 N-甲基哌嗪基二芳基哌啶酮 (L-2663) 及其前氮氧化物偶联物 (HO-4589) 对人类胰腺癌 (AsPC-1) 细胞系和异种移植肿瘤的抗癌功效老鼠。使用流式细胞术，我们确定了 L-2663 和 HO-4589 药物在诱导线粒体毒性、触发细胞周期停滞和细胞凋亡方面的作用。EPR 光谱用于量化细胞中 HO-4589 的细胞摄取、代谢转化和稳定性，并在体内监测肿瘤氧合作为生长的函数。结果确定了 L-2663 和 HO-4589 化合物的不同抗增殖功效，对癌细胞具有靶向作用，同时对非癌细胞的毒性较小。该研究可能对未来设计用于治疗胰腺癌的安全有效的化疗药物具有重要意义。